RESUMO
The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.
Assuntos
Antineoplásicos , Azóis , Compostos Ferrosos , Compostos Heterocíclicos , Metalocenos , Azóis/química , Azóis/farmacologia , Azóis/síntese química , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Compostos Ferrosos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Metalocenos/química , Metalocenos/farmacologia , Metalocenos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese químicaRESUMO
Sonodynamic therapy (SDT) has been extensively studied as a new type of non-invasive treatment for mammary cancer. However, the poor water solubility and defective biocompatibility of sonosensitizers during SDT hinder the sonodynamic efficacy. Herein, a nanoplatform has been developed to achieve high efficient SDT against mammary cancer through the host-guest interaction of ß-cyclodextrin/5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (ß-CD-TPP) and ferrocenecarboxylic acid/chitooligosaccharides (FC-COS). Moreover, the glucose oxidase (GOx) was loaded through electrostatic adsorption, which efficiently restricts the energy supply in tumor tissues, thus enhancing the therapeutic efficacy of SDT for tumors. Under optimal conditions, the entire system exhibited favorable water solubility, suitable particle size and viable biocompatibility. This facilitated the integration of the characteristics of starvation therapy and sonodynamic therapy, resulting in efficient inhibition of tumor growth with minimal side effects in vivo. This work may provide new insights into the application of natural oligosaccharides for construct multifunctional nanocarrier systems, which could optimize the design and development of sonodynamic therapy strategies and even combination therapy strategies.
Assuntos
Quitosana , Oligossacarídeos , Espécies Reativas de Oxigênio , Terapia por Ultrassom , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Animais , Quitosana/química , Quitosana/farmacologia , Feminino , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Terapia por Ultrassom/métodos , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Glucose Oxidase/metabolismo , Glucose Oxidase/química , Nanopartículas/química , Quitina/química , Quitina/análogos & derivados , Quitina/farmacologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Neoplasias da Mama/terapia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Metalocenos/química , Metalocenos/farmacologia , Porfirinas/química , Porfirinas/farmacologiaRESUMO
Human African trypanosomiasis (HAT, sleeping sickness) and American trypanosomiasis (Chagas disease) are endemic zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Trypanosoma cruzi, respectively). Just a few old drugs are available for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. Only fexinidazole has been recently incorporated into the arsenal for the treatment of HAT. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these pathogens by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: pyridine-2-thiolato-1-oxide ligand (mpo) and polypyridyl ligands (NN). Three [Ru(mpo)(dppf)(NN)](PF6) compounds and their derivatives with chloride as a counterion were synthesized and fully characterized in solid state and solution. They showed in vitro activity on bloodstream T. brucei (EC50 = 31-160 nM) and on T. cruzi trypomastigotes (EC50 = 190-410 nM). Compounds showed the lowest EC50 values on T. brucei when compared to the whole set of metal-based compounds previously developed by us. In addition, several of the Ru compounds showed good selectivity toward the parasites, particularly against the highly proliferative bloodstream form of T. brucei. Interaction with DNA and generation of reactive oxygen species (ROS) were ruled out as potential targets and modes of action of the Ru compounds. Biochemical assays and in silico analysis led to the insight that they are able to inhibit the NADH-dependent fumarate reductase from T. cruzi. One representative hit induced a mild oxidation of low molecular weight thiols in T. brucei. The compounds were stable for at least 72 h in two different media and more lipophilic than both bioactive ligands, mpo and NN. An initial assessment of the therapeutic efficacy of one of the most potent and selective candidates, [Ru(mpo)(dppf)(bipy)]Cl, was performed using a murine infection model of acute African trypanosomiasis. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described, but was unable to control parasite proliferation in vivo, probably because of its rapid clearance or low biodistribution in the extracellular fluids. Future studies should investigate the pharmacokinetics of this compound in vivo and involve further research to gain deeper insight into the mechanism of action of the compounds.
Assuntos
Compostos Ferrosos , Rutênio , Tripanossomicidas , Trypanosoma cruzi , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Compostos Ferrosos/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Ligantes , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Animais , Rutênio/química , Rutênio/farmacologia , Camundongos , Metalocenos/química , Metalocenos/farmacologia , Metalocenos/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Estrutura Molecular , Compostos Organometálicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese químicaRESUMO
To overcome the low efficacy of sonodynamic therapy (SDT) caused by hypoxia in the tumor microenvironment, we developed a multiple anti-tumor nanoplatform with synergistic SDT, photothermal therapy (PTT), and ferroptosis effects. PCN-224@FcCaO2/Mn/dihydroartemisinin/imiquimod/PDA (PFC) was prepared by modified with dihydroartemisinin (DHA), imiquimod (R837), CaO2, ferrocene (Fc) and Mn2+ on the PCN-224 (Cu) to achieve self-replenishment of H2O2/O2 and GSH consumption. FcCaO2 decomposed into H2O2 in the tumor microenvironment, triggering the Fenton effect to produce OH, and Cu2+ reduced the potential loss of OH by the depletion of GSH. Under ultrasonic (US) and laser irradiation, PFC exhibits exciting PTT and SDT effects from polydopamine (PDA) and PCN-224. Mn2+ not only promoted the reaction of H2O2 to produce O2 to effectively enhance SDT but also induced tumor cell apoptosis by Mn2+ combined with DHA. PFC induced ferroptosis via Fe interaction with DHA to produce ROS and reduce the expression of GPX4. The released R837 and tumor-associated antigens from SDT/PTT can produce damage associated molecular patterns (DAMPs), which can initiate adaptive immune responses to kill cancer cells, and released again to promote the tumor immune cycle. What's more, SDT/PTT and ferroptosis combined with aPD-L1 can effectively suppress both primary and distant tumor growth.
Assuntos
Indóis , Estruturas Metalorgânicas , Terapia Fototérmica , Polímeros , Indóis/química , Indóis/farmacologia , Polímeros/química , Polímeros/farmacologia , Humanos , Animais , Camundongos , Terapia Fototérmica/métodos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Linhagem Celular Tumoral , Nanopartículas/química , Apoptose/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Terapia Combinada , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/química , Peróxido de Hidrogênio/farmacologia , Imiquimode/farmacologia , Metalocenos/química , Metalocenos/farmacologiaRESUMO
We have red-shifted the light absorbance property of a Re(I)-tricarbonyl complex via distant conjugation of a ferrocene moiety and developed a novel complex ReFctp, [Re(Fctp)(CO)3Cl], where Fctp = 4'-ferrocenyl-2,2':6',2â³-terpyridine. ReFctp showed green to red light absorption ability and blue emission, indicating its potential for photodynamic therapy (PDT) application. The conjugation of ferrocene introduced ferrocene-based transitions, which lie at a higher wavelength within the PDT therapeutic window. The time-dependent density functional theory and excited state calculations revealed an efficient intersystem crossing for ReFctp, which is helpful for PDT. ReFctp elicited both PDT type I and type II pathways for reactive oxygen species (ROS) generation and facilitated NADH (1,4-dihydro-nicotinamide adenine dinucleotide) oxidation upon exposure to visible light. Importantly, ReFctp showed effective penetration through the layers of clinically relevant 3D multicellular tumor spheroids and localized primarily in mitochondria (Pearson's correlation coefficient, PCC = 0.65) of A549 cancer cells. ReFctp produced more than 20 times higher phototoxicity (IC50 â¼1.5 µM) by inducing ROS generation and altering mitochondrial membrane potential in A549 cancer cells than the nonferrocene analogue Retp, [Re(CO)3(tp)Cl], where tp = 2,2':6',2â³-terpyridine. ReFctp induced apoptotic mode of cell death with a notable photocytotoxicity index (PI, PI = IC50dark/IC50light) and selectivity index (SI, SI = normal cell's IC50dark/cancer cell's IC50light) in the range of 25-33.
Assuntos
Antineoplásicos , Compostos Ferrosos , Luz , Metalocenos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Humanos , Metalocenos/química , Metalocenos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/efeitos da radiação , Antineoplásicos/síntese química , Espécies Reativas de Oxigênio/metabolismo , Teoria da Densidade Funcional , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/efeitos da radiação , Complexos de Coordenação/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Luz VermelhaRESUMO
Ferrocene, ruthenium(II) and iridium(III) organometallic complexes, potential substitutes for platinum-based drugs, have shown good application prospects in the field of cancer therapy. Therefore, in this paper, six ferrocene-modified half-sandwich ruthenium(II) and iridium(III) propionylhydrazone complexes were prepared, and the anticancer potential was evaluated and compared with cisplatin. These complexes showed potential in-vitro anti-proliferative activity against A549 cancer cells, especially for Ir-based complexes, and showing favorable synergistic anticancer effect. Meanwhile, these complexes showed little cytotoxicity and effective anti-migration activity. Ir3, the most active complex (ferrocene-appended iridium(III) complex), could accumulate in the intracellular mitochondria, disturb the cell cycle (S-phase), induce the accumulation of reactive oxygen species, and eventually cause the apoptosis of A549 cells. Then, the design of these complexes provides a good structural basis for the multi-active nonplatinum organometallic anticancer complexes.
Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Compostos Ferrosos , Hidrazonas , Irídio , Metalocenos , Rutênio , Humanos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Irídio/química , Irídio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Metalocenos/química , Metalocenos/farmacologia , Rutênio/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Células A549 , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacosRESUMO
A small-molecule Fenton reagent, integrating ferrocene with a carbonic anhydrase inhibitor, was designed to intelligently regulate intracellular acidosis for self-augmented chemodynamic therapy. Acidosis coupled with up-regulated ROS levels demonstrated potent cytotoxicity and effective tumor suppression.
Assuntos
Compostos Ferrosos , Peróxido de Hidrogênio , Ferro , Metalocenos , Humanos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Ferro/química , Metalocenos/química , Metalocenos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Acidose/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , CamundongosRESUMO
The therapeutic outcome of chemodynamic therapy (CDT) is greatly hindered by the presence of oxidative damage repair proteins (MTH1) inside cancer cells. These oxidative damage repair proteins detoxify the action of radicals generated by Fenton or Fenton-like reactions. Hence, it is extremely important to develop a simple strategy for the downregulation of MTH1 protein inside cancer cells along with the delivery of metal ions into cancer cells. A one-pot host-guest supramolecular approach for the codelivery of MTH1 siRNA and metal ions into a cancer cell is reported. Our approach involves the fabrication of an inclusion complex between cationic ß-cyclodextrin and a ferrocene prodrug, which spontaneously undergoes amphiphilicity-driven self-assembly to form spherical nanoparticles (NPs) having a positively charged surface. The cationic surface of the NPs was then explored for the loading of MTH1 siRNA through electrostatic interactions. Using HeLa cells as a representative example, efficient uptake of the NPs, delivery of MTH1 siRNA and the enhanced CDT of the nanoformulation are demonstrated. This work highlights the potential of the supramolecular approach as a simple yet efficient method for the delivery of siRNA across the cell membrane for enhanced chemodynamic therapy.
Assuntos
Ciclodextrinas , Compostos Ferrosos , Nanopartículas , Neoplasias , Humanos , RNA Interferente Pequeno , Células HeLa , Metalocenos/farmacologia , Nanopartículas/uso terapêutico , Cátions , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Peróxido de Hidrogênio/uso terapêuticoRESUMO
Ferrocene derivatives show a wide range of pharmacological activities in the medical field, especially in the anti-tumor field, and can be used as candidate drugs or lead compounds for the treatment of tumors and other diseases. And α-phenethylamine is an important intermediate for the preparation of fine chemical products. (R)-(+)-1-Phenethylamine ferrocenecarboxylic acid/(S)-(-)-1-phenethylamine ferrocenecarboxylic acid were prepared, named compounds 1 and 2, respectively. Single crystal X-ray diffraction showed that compounds 1 and 2 crystallized in the orthorhombic system space group P21 21 21 , and the crystal structures of compounds 1 and 2 exhibited mirror symmetry. The inhibitory effect of two compounds on SW480, MDA-MB-231, and H1299 cells was tested by MTT colorimetry. The IC50 values of the compounds against cancer cells were also calculated. The anti-cancer effect was more pronounced for compounds in the S-configuration. Compound 2 made the wild-type cancer cells undergo apoptosis, thus preventing cancer; it also had the function of helping the cell gene repair defects.
Assuntos
Antineoplásicos , Compostos Ferrosos , Fenetilaminas , Metalocenos/farmacologia , Metalocenos/química , Linhagem Celular Tumoral , Estereoisomerismo , Antineoplásicos/farmacologia , Antineoplásicos/químicaRESUMO
We report the design, synthesis, and in vitro evaluation of stimuli-responsive nanoscale micelles that can be activated by light to induce a cytotoxic effect. Micelles were assembled from amphiphilic units made of a photoactivatable ferrocenyl linker, connected on one side to a lipophilic chain, and on the other side to a hydrophilic pegylated chain. In vitro experiments indicated that pristine micelles ("off" state) were nontoxic to MCF-7 cancer cells, even at high concentrations, but became potent upon photoactivation ("on" state). The illumination process led to the dissociation of the micelles and the concomitant release of iron species, triggering cytotoxicity.
Assuntos
Antineoplásicos , Compostos Ferrosos , Micelas , Metalocenos/farmacologia , FototerapiaRESUMO
Ferrocenyl derivatives and organometallic iridium(III) complexes have been prospective substitutes for platinum-based anticancer drugs. Eight half-sandwich iridium(III) ferrocene-thiosemicarbazide (Fc-TSC) Schiff base anticancer complexes were prepared in this study. These complexes displayed a dimeric structure and exhibited a particular fluorescence due to the "enol" orientation of the TSC pro-ligand. An energy-dependent pathway of the uptake mechanism was ascertained, which ended in the lysosome and led to lysosome damage and apoptosis. Flow cytometry confirmed that the complexes could block the cell cycle (G1 phase) and improve the levels of intracellular reactive oxygen species, indicating an anticancer mechanism of oxidation. Then, a lysosomal-mitochondrial anticancer pathway was verified through western blotting. In vivo toxicity assays confirmed that these complexes showed better anti-migration ability and less toxicity in comparison to cisplatin. Thus, these complexes provide a new strategy for the design of non-platinum organometallic anticancer drugs.
Assuntos
Antineoplásicos , Complexos de Coordenação , Irídio/farmacologia , Irídio/química , Bases de Schiff/farmacologia , Metalocenos/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Estudos Prospectivos , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Linhagem Celular TumoralRESUMO
An effective synthetic protocol towards the oxidation of sumanene-ferrocene conjugates bearing one to four ferrocene moieties has been established. The oxidation protocol was based on the transformation of FeII from ferrocene to FeIII-containing ferrocenium cations by means of the treatment of the title organometallic buckybowls with a mild oxidant. Successful isolation of these ferrocenium-tethered sumanene derivatives 5-7 gave rise to the biological evaluation of the first, buckybowl-based anticancer agents, as elucidated by in vitro assays with human breast adenocarcinoma cells (MDA-MB-231) and embryotoxicity trials in zebrafish embryos supported with in silico toxicology studies. The designed ferrocenium-tethered sumanene derivatives featured attractive properties in terms of their use in cancer treatments in humans. The tetra-ferrocenium sumanene derivative 7 featured especially beneficial biological features, elucidated by low (<40% for 10 µM) viabilities of MDA-MB-231 cancer cells together with a 1.4-1.7-fold higher viability of normal cells (human mammary fibroblasts, HMF) for respective concentrations. Compound 7 featured significant cytotoxicity against cancer cells thanks to the presence of sumanene and ferrocenium moieties; the latter motif also provided the selectivity of anticancer action. The biological properties of 7 were also improved in comparison with those of native building blocks, which suggested the effects of the presence of the sumanene skeleton towards the anticancer action of this molecule. Ferrocenium-tethered sumanene derivatives exhibited potential towards the generation of reactive oxygen species (ROS), responsible for biological damage to the cancer cells, with the most efficient generation of the tetra-ferrocenium sumanene derivative 7. Derivative 7 also did not show any embryotoxicity in zebrafish embryos at the tested concentrations, which supports its potential as an effective and cancer-specific anticancer agent. In silico computational analysis also showed no chromosomal aberrations and no mutation with AMES tests for the compound 7 tested with and without microsomal rat liver fractions, which supports its further use as a potent drug candidate in detailed anticancer studies.
Assuntos
Antineoplásicos , Peixe-Zebra , Humanos , Animais , Metalocenos/farmacologia , Compostos Férricos , Compostos Ferrosos/farmacologia , Antineoplásicos/farmacologiaRESUMO
Half-sandwich iridium(III) (IrIII) complexes and ferrocenyl (Fc) derivatives are becoming the research hotspot in the field of anticancer because of their good bioactivity and unique anticancer mechanism different from platinum-based drugs. Then, a series of half-sandwich IrIII-Fc pyridine complexes have been prepared through the structural regulation in this study. The incorporation of half-sandwich IrIII complex with Fc unit successfully improves their anticancer activity, and the optimal performance (IrFc5) is almost 3-fold higher than that of cisplatin against A549 cells, meanwhile, which also shows better anti-proliferative activity against A549/DDP cells. Complexes can aggregate in the intracellular lysosome of A549 cells and induce lysosomal damage, disrupt the cell cycle, increase the level of intracellular reactive oxygen species, and eventually lead to cell apoptosis. Half-sandwich IrIII-Fc heteronuclear metal complexes possess a different anticancer mechanism from cisplatin, which can serve as a potential alternative to platinum-based drugs and show a good application prospect.
Assuntos
Antineoplásicos , Complexos de Coordenação , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Cisplatino/farmacologia , Irídio/farmacologia , Irídio/química , Metalocenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose , Linhagem Celular TumoralRESUMO
The effects of ferrocene (Fc) and ferrocenium (Fc+) induced in triple negative human breast cancer MCF-7 cells were explored by immunofluorescence, flow cytometry, and transmission electron microscopy analysis. The different abilities of Fc and Fc+ to produce reactive oxygen species and induce oxidative stress were clearly observed by activating apoptosis and morphological changes after treatment, but also after tests performed on the model organism D. discoideum, particularly in the case of Fc+. The induction of ferroptosis, an iron-dependent form of regulated cell death driven by an overload of lipid peroxides in cellular membranes, occurred after 2 h of treatment with Fc+ but not Fc. However, the more stable Fc showed its effects by activating necroptosis after a longer-lasting treatment. The differences observed in terms of cell death mechanisms and timing may be due to rapid interconversion between the two oxidative forms of internalized iron species (from Fe2+ to Fe3+ and vice versa). Potential limitations include the fact that iron metabolism and mitophagy have not been investigated. However, the ability of both Fc and Fc+ to trigger different and interregulated types of cell death makes them suitable to potentially overcome the shortcomings of traditional apoptosis-mediated anticancer therapies.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Células MCF-7 , Metalocenos/farmacologia , Apoptose/fisiologia , Ferro/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Ras proteins are membrane-bound GTPases that regulate essential cellular processes at the plasma membrane (PM). Constitutively active mutations of K-Ras, one of the three Ras isoforms in mammalian cells, are frequently found in human cancers. Ferrocene derivatives, which elevate cellular reactive oxygen species (ROS), have shown to block the growth of non-small cell lung cancers harboring oncogenic mutant K-Ras. Here, we tested a novel ferrocene derivative on the growth of pancreatic ductal adenocarcinoma and non-small cell lung cancer. Our compound, which elevated cellular ROS levels, inhibited the growth of K-Ras-driven cancers, and abrogated the PM binding and signaling of K-Ras in an isoform-specific manner. These effects were reversed upon antioxidant supplementation, suggesting a ROS-mediated mechanism. We further identified that K-Ras His95 residue plays an important role in this process, and it is putatively oxidized by cellular ROS. Together, our study demonstrates that the redox system directly regulates K-Ras/PM binding and signaling via oxidative modification at the His95, and proposes a role of oncogenic mutant K-Ras in the recently described antioxidant-induced growth and metastasis of K-Ras-driven cancers.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias Pancreáticas , Humanos , Animais , Antioxidantes , Metalocenos/farmacologia , Espécies Reativas de Oxigênio , Oxirredução , Estresse Oxidativo , MamíferosRESUMO
BACKGROUND: Antimicrobial resistance is an emerging global health challenge that has led researchers to study alternatives to conventional antibiotics. A promising alternative is antimicrobial peptides (AMPs), produced as the first line of defense by almost all living organisms. To improve its biological activity, the conjugation of AMPs is a promising approach. OBJECTIVE: In this study, we evaluated the N-terminal conjugation of p-Bt (a peptide derived from Bothrops Jararacuçu`s venom) with ferrocene (Fc) and gallic acid (GA). Acetylated and linear versions of p-Bt were also synthesized to evaluate the importance of N-terminal charge and dimeric structure. METHODS: The compounds were obtained using solid-phase peptide synthesis. Circular dichroism, vesicle permeabilization, antimicrobial activity, and cytotoxicity studies were conducted. RESULTS: No increase in antibacterial activity against Escherichia coli was observed by adding either Fc or GA to p-Bt. However, Fc-p-Bt and GA-p-Bt exhibited improved activity against Staphylococcus aureus. No cytotoxicity upon fibroblast was observed for GA-p-Bt. On the other hand, conjugation with Fc increased cytotoxicity. This toxicity may be related to the membrane permeabilization capacity of this bioconjugate, which showed the highest carboxyfluorescein leakage in vesicle permeabilization experiments. CONCLUSION: Considering these observations, our findings highlight the importance of adding bioactive organic compounds in the N-terminal position as a tool to modulate the activity of AMPs.
Assuntos
Peptídeos Catiônicos Antimicrobianos , Ácido Gálico , Antibacterianos/farmacologia , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Escherichia coli , Ácido Gálico/farmacologia , Metalocenos/farmacologia , Testes de Sensibilidade Microbiana , Peptídeos/química , Peptídeos/farmacologia , Lisina/química , Lisina/farmacologiaRESUMO
Moderate oxygen (O2) supply and uneven distribution of oxygen at the tumor site usually hinder the therapeutic efficacy of hypoxia-activated prodrugs. In this report, we designed a ferrocene-containing supramolecular nanomedicine (PFC/GOD-TPZ) with the PEG corona and disulfide-bond cross-linked core to co-encapsulate 4-di-N-oxide tirapazamine (TPZ) and glucose oxidase (GOD). The PEG corona of PFC/GOD-TPZ could be weakly acidic tumor pH-responsively detached for an enhanced cellular internalization, while the disulfide-bond cross-linked core could be cleavaged by intracellular glutathione (GSH) to present a GSH-triggered drug-release behavior. Subsequently, the cascade reactions, including catalytic reactions among the released GOD, glucose, and O2 to generate H2O2 and the subsequent Fenton reaction between ferrocene and H2O2, occurred. With the depletion of O2, the non-toxic TPZ was activated and converted into the cytotoxic therapeutic agent benzotriazinyl (BTZ) radical under the exacerbated hypoxic microenvironment. Collectively, the PFC/GOD-TPZ provides a promising strategy for effective combination therapy of GOD-mediated starvation therapy, chemodynamic therapy (CDT), and hypoxia-activated chemotherapy (CT).
Assuntos
Antineoplásicos , Neoplasias , Humanos , Nanomedicina , Metalocenos/farmacologia , Metalocenos/uso terapêutico , Peróxido de Hidrogênio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Tirapazamina/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oxigênio , Hipóxia/tratamento farmacológico , Glutationa , Dissulfetos/farmacologia , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
To improve the antiproliferative effect of ALC67 (diastereomeric mixture of ethyl 2-phenyl-3-propioloyl-1,3-thiazolidine-4-carboxylate), its structure was modified via (i) bioisosteric substitution of the phenyl ring by the ferrocene unit and (ii) replacing the propiolamide side-chain in ACL67 with other acyl groups having differing electrophilicities. In this way, a small library of methyl N-acyl-2-ferrocenyl-1,3-thiazolidine-4-carboxylates (13 compounds in total) was created and characterized by spectral and crystallographic means. The last N-acylation step was highly diastereoselective toward the cis-diastereomer. In solution, most of the obtained compounds existed as a mixture of two rotamers and displayed a preference for the syn-orientation around the CN bond. A twisted 5T4 envelope conformation was adopted by the derivative containing the N-phenoxyacetyl group in the crystalline state. Two derivatives with chloroacetyl and bromoacetyl groups in the N-3 side chain were cytotoxic to fibroblasts and hepatocellular cancer cells in the low micromolar range (IC50(MRC5) = 9.0 and 11.8 µM, respectively, and IC50(HepG2) = 10.6 and 18.4 µM, respectively) causing an effect similar to the lead compound (IC50(HepG2) = 10.0 µM) and cisplatin (IC50(MRC5) = 4.0 µM and IC50(HepG2) = 7.7 µM). Several derivatives also manifested modest antimicrobial effects against the studied microbial strains (MICs in the range from 0.44 to 4.0 µmol/mL). Our findings demonstrated that the introduction of a ferrocene core facilitated the preparation of optically pure analogs of ALC67 and that the cytotoxicity of compounds may be enhanced by adding proper electrophilic centers to the N-acyl side-chain.
Assuntos
Anti-Infecciosos , Antineoplásicos , Tiazolidinas/farmacologia , Metalocenos/farmacologia , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Anti-Infecciosos/farmacologia , Proliferação de CélulasRESUMO
Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1 = 1.90±0.12 mM-1 s-1 and r2 = 12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic â¢OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.
Assuntos
Nanopartículas , Neoplasias , Selênio , Humanos , Meios de Contraste/farmacologia , Meios de Contraste/química , Metalocenos/farmacologia , Prótons , Peróxido de Hidrogênio/farmacologia , Gadolínio/química , Nanopartículas/química , Imageamento por Ressonância Magnética/métodos , Água , Imagem Multimodal , Microambiente TumoralRESUMO
Besides the use of resveratrol as a drug candidate, there are obstacles mainly due to its poor pharmacokinetic properties. Numerous studies are being conducted on the synthesis of resveratrol derivatives that exhibit enhanced biological activity. The aim of our research was to investigate activity of the newly synthesized ferrocene-containing triacyl derivative of resveratrol to achieve cell protection from endo/exogenous ROS and reduction in cell death by assessing multiple endpoints. Our research showed that both resveratrol and the resveratrol derivatives (1-100 µM) lower the levels of ROS in CHO-K1 cells. Resveratrol at doses <20 µM had little or no effect on cell proliferation, while at higher doses, a significant inhibitory effect on cell proliferation and viability has been noticed. The activity of the new derivative was significantly altered compared to resveratrol-cellular viability was not suppressed regardless of the concentration applied, and the extent of apoptosis was low. In summary, the new ferrocene-resveratrol derivative has the potential to protect cells from oxidative stress due to its low cytotoxicity and retained antioxidant properties, whereas caution should be exercised with resveratrol at higher doses, as it significantly impairs cell viability and induces cell death. By linking ROS to specific diseases (relevance in neurodegenerative, cardiovascular, and neoplastic diseases), we can assume that the new resveratrol derivative can prevent or alleviate the mentioned disorders. Furthermore, recognition of the resveratrol derivative as an anti-apoptotic chemical could be useful in the cultivation of various cell lines on a large scale in the industrial biotechnology.